Of the 350,000 people surviving stroke each year in the United States, approximately 200,000 have persistent and disabling deficits. The mechanisms of stroke recovery are unknown and therefore poorly manipulated by existing therapeutic interventions. Modulatory therapies such as forced-use or constraintinduced therapy, pharmaco-therapy, and cell transplantation have been employed in stroke recovery over recent years; however, these therapies are commonly investigated in selected groups of chronic stroke subjects and the appropriate timing for such interventions is largely unknown and in most cases is not based on anatomic or physiologic information. In this proposal, we combine a brain imaging technique, functional magnetic resonance imaging (fMRI), with an electrophysiological technique, transcranial magnetic stimulation (TMS), to investigate how the anatomical and physiological processes interact following injury during the active recovery period and to determine their functional importance for recovery. This combined technology approach to stroke recovery is the most innovative aspect of this proposal and it permits us to gather data unavailable by employing each technology alone. In the current literature there is contradictory evidence over whether following stroke, during motor recovery, the ipsilateral, unaffected, sensorimotor cortex and its uncrossed corticospinal tract take over the role of the contralateral, affected, sensorimotor cortex and/or corticospinal tract. In two sequential experiments we propose to use the combined fMRI and TMS approach to address this specific question and to examine other candidate regions in motor recovery following stroke. Our specific aims are, in experiment one, to determine at four clinically-defined stages of recovery a) the activation pattern of recovering movements using fMRI and correlate it to b) the integrity of ipsi- and contralateral corticospinal tracts and the measures of cortico-cortico excitability using TMS and in experiment 2, to determine whether inhibition of the ipsilateral sensorimotor cortex activation with repetitiveTMS (rTMS) temporarily affects motor performance in the recovering hand. We hypothesize that ipsilateral motor cortex, although activated on movement of the recovering hand, is non-functional and perhaps hinders recovery and that other activated cortical areas are associated with return of good hand function. Identifying the critical areas and interactions of the motor network that enable recovery and the critical timepoints during which they become important, will direct the application of existing, and the development of new modulatory therapies to improve outcome and reduce disabilities for stroke survivors.